This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In 2007, UNAIDS reported that women comprise 61% of adults in Sub-Saharan Africa living with HIV/AIDS. This highlights the critical need for an effective, female-controlled HIV prevention strategy such as a vaginally-applied microbicide gel, which can enable women to protect themselves from acquiring HIV. First-generation microbicides that had detergent-like activities proved ineffective and have fueled interest in expanding our research efforts on developing topical microbicide gels formulated with antiretroviral (ARV) drugs. Unlike first-generation, these gels are more promising because they can deliver a high dose of potent drugs that can block HIV replication at the mucosal point of entry. To this end, we have successfully formulated and evaluated several gels containing single or combinations of nucleoside/nucleotide reverse transcriptase (emtricitabine and tenofovir) or integrase (L-870812) inhibitors. We have completed efficacy studies for two gels containing tenofovir (TFV) alone or in combination with emtricitabine (FTC) against vaginal transmission using a repeat-challenge macaque model. Both gels were fully protective indicating that drug combinations may not be needed for effective topical prophylaxis. In addition, we have initiated another study to evaluate the window of protection by the tenofovir gel and examine efficacy when virus exposure occurs 3 days after gel application. We also completed a pilot study to assess the efficacy of a gel with an integrase inhibitor and show that it was highly protective demonstrating for the first time the utility of this class of drugs. Our results highlight the high efficacy of topical antiretroviral prophylaxis as a biomedical prevention strategy, support clinical trials in humans, and inform their design by identifying highly effective modalities.